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The soluble factor milieu in IPF and in COPD exacerbations dysregulates epithelial differentiation

ABSTRACT: In idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), epithelial abnormalities are present including bronchiolization and alveolar cell death and dysfunction. As epithelial progenitor cells are directed by their microenvironment, we hypothesized that changes in the microenvironment disrupt normal epithelial growth and differentiation. We therefore mimicked the soluble factor microenvironment in IPF using an IPF cocktail (IPFc), composed of 9 factors which are increased in IPF lungs (CCL2, IL-1β, IL-4, IL-8, IL-13, IL-33, TGF-β, TNFα and TSLP) and in COPD exacerbations using an exacerbation cocktail (EC) composed of 4 factors that are increased during an exacerbation of COPD (TNFα, IL-1β, IL-6, IL-8). We asked whether the soluble factor milieu in IPF and COPD exacerbations affects epithelial growth and differentiation. Mouse lung organoids (primary EpCAM+ cells co-cultured with CCL206 fibroblasts) were used to study epithelial growth and differentiation. Organoids exposed to IPFc, EC or TGF-β (as a comparator) were resorted into EpCAM+ and CCL206 fractions, and subjected to RNA-sequencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE245259 | GEO | 2024/04/30

REPOSITORIES: GEO

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Project description:BACKGROUND: Chronic obstructive pulmonary disease (COPD) exacerbations significantly contribute to morbidity and mortality. The complex nature of COPD presents challenges in accurately predicting and understanding frequent exacerbations.OBJECTIVE: This study aimed to investigate the metabolic characteristics of frequent exacerbation of COPD (COPD-FE) phenotype, identify potential metabolic biomarkers associated with COPD-FE risk and explore underlying pathogenic mechanisms.METHODS: An internal cohort of 30 stable COPD patients was recruited. A widely targeted metabolomics approach was employed to detect and compare serum metabolite expressions between patients with COPD-FE and non-frequent exacerbations (COPD-NE). Subsequently, bioinformatics analysis was utilized for pathway enrichment of the identified metabolites; Spearman correlation analysis explored associations between metabolites and clinical indicators, and receiver operating characteristic (ROC) analysis assessed the predictive performance of identified metabolites. An external cohort of 20 patients with COPD validated findings from the internal cohort.RESULTS: Out of 484 detected metabolites, 25 exhibited significant differences between COPD-FE and COPD-NE. Metabolomic analysis revealed differences in lipid, energy, amino acid and immunity pathways. Spearman correlation analysis showed associations between metabolites and clinical indicators of acute exacerbation risk. ROC analysis revealed that D-fructose 1,6-bisphosphate (AUC=0.871), arginine (AUC=0.836), L-2-Hydroxyglutarate (L-2HG, AUC=0.849), Diacylglycerol (DG)(16:0/20:5) (AUC=0.827), DG(16:0/20:4) (AUC=0.818) and carnitine-C18:2 (AUC=0.804) had area under the curve (AUC) values above 0.8, highlighting their superior discriminative capacity between the two groups. External validation results showed that DG(16:0/20:5), DG(16:0/20:4), carnitine-C18:2 and L-2HG were significantly different between COPD-FE patients and COPD-NE patients (p-value<0.05).CONCLUSION: This study offers insights into early identification, mechanistic understanding and personalized management of COPD-FE phenotype.

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The soluble factor milieu in IPF and in COPD exacerbations dysregulates epithelial differentiation

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